Artemether treatment of prepatent Schistosoma japonicum induces resistance to reinfection in association with reduced pathology

Abstract

Artemether (ART) is a well-described antimalarial with efficacy against juvenile schistosomes, with 7-day-old schistosomula being particularly susceptible. Both ART-affected worms and parasites developing from irradiated cercariae die at similar times after infection. Our aim was to determine if ART treatment of prepatent schistosomiasis japonica may result in the generation of a protective immune response. Female CBA mice were treated with a single dose of ART at defined time points after percutaneous infection with a virulent Chinese mainland strain of Schistosoma japonicum. Half of the mouse cohorts were subjected to homologous parasite strain reinfection after drug treatment to assess protective effects of ART therapy. Two independent trials demonstrated that a statistically significant (58% and 50%) reduction in challenge worm burden occurred after reinfection of those mice treated with ART at two weeks p.i. A reduction in the IL-4 response to soluble worm antigen preparation (SWAP) was also seen in ART-treated mice but with no correlation to reinfection resistance. In the Chinese mainland strain used, ART treatment of prepatent infection at the appropriate time point induced resistance to reinfection. There was also an anti-pathology effect observed in ART-treated mice that remained significant after reinfection.

Figure 1

Quantification of egg-induced liver pathology by measurement of mean granuloma diameter (in millimeters ± SD) and hepatic granuloma volume density (expressed as percent of section volume ± SD). Panels A and C display granuloma diameter and hepatic granuloma volume density from the baseline infection groups. Panels B and D display data from the groups reinfected following ART-treatment. The two-tailed t test was used for statistical comparisons in panels A and B (* = P < 0.0001 versus Control-1B or Control-1A, respectively). Statistical comparisons in panels C and D were made using the Likelihood Ratio Method (* = P < 0.0001 compared with either Control-1B or Control-1A, respectively). Neither granuloma diameter nor granuloma volume density was significantly different from the challenge control group (Control-2) for mice reinfected after ART treatment.

Figure 2

IL-4 production by splenic lymphocytes cultured for 72 h in SWAP. Results are the mean (± 1 SD) obtained from both Trials 1 and 2. * = P < 0.01 Compared with Control-1A; # = P < 0.01 compared with Control-2 (two-tailed t test).